The inflammatory response is mediated by cytokines, and cytokine activity and expression in turn are regulated by kinases. Aberrant kinase and cytokine activity play pivotal roles in chronic and acute inflammatory diseases. Aberrant kinase and cytokine activity also underly autoimmune diseases and different types of cancer.
Kinase inhibitors are an established class of anticancer drugs (Chen, J Nat Prod, 2012, 75 (12):2269-2269) and anti-inflammation drugs (Wang et al., J Immunol, 2013, 191(3):1164-1174). For example, Janus Kinase 2 (JAK2) and Janus Kinase 3 (JAK3) are tyrosine kinases that regulate transcription of various target genes involved in growth and proliferation (Reiter et al., Cancer Res, 2005, 65(7):2662-2667; Takemoto et al., Proc Natl Acad Sci USA, 1997, 94(25):13897-13902). JAK2 and JAK3 are also involved in mediating the signaling of many inflammatory cytokines involved in inflammation (Wang et al., J Immunol, 2013, 191(3):1164-1174). JAK2 and JAK 3 inhibitors are therefore useful in treating cancers, and autoimmune and inflammatory diseases (Fridman et al., J Invest Dermatol, 2011, 131(9):1838-1844). p38α (p38 mitogen-activated protein kinase alpha) is a MAP (Mitogen-activated protein) kinase that also mediates the signaling of many inflammatory cytokines involved in inflammation. Inhibitors of the kinase activity of p38 α are therefore useful anti-inflammatory agents (Daniele et al., Cell Signal, 2015, 27(8):1609-1629). Glycogen synthase kinase 3 beta (GSK3β) is a serine-threonine kinase that regulates p53 function in proliferating cells such as cancer cells (WO2006/006939) and its inhibition down regulates inflammatory cytokines (Li et al., Cell Physiol Biochem, 2013, 32(6):1720-1728). Lymphocyte-specific protein tyrosine kinase (LCK) is a Src tyrosine kinase involved in T cell activation and proliferation (Hanke et al., Inflamm Res, 1995, 44:357; Bolen et al., Ann Rev Immunol, 1997, 15:371). LCK inhibition has been successful in treatment of inflammatory diseases (Brisslert et al., Biochem Biophys Acta, 2014, 1842(11):2049-2059). Inhibition of the IκB kinase (IKK) β subunit of the IKK kinase enzyme complex has also been associated with anti-inflammatory effects (Novoselova et al., Mediators Inflamm, 2014, 2014:724838). CLK (CDC2-like kinase) plays important roles in gene splicing and is a potential therapeutic target for Alzheimer's disease (Jain et al., Curr Drug Targets, 2014, 15(5):539-550).
Cytokines play important roles in initiating and regulating immune responses, and therefore their inhibition is a well-established approach to controlling autoimmune and inflammatory diseases (Kopf et al., Nature Reviews Drug Discovery, September 2010, 9:703-718). Exemplary cytokine targets include Interleukin-1β (IL-1β) (Xu et al., Clin Exp Pharmacol Physiol, 2015, 42(10): 1075-83), Interleukin-2 (IL-2) (Roediger et al., J Allergy Clin Immunol, 2015, 136(6):1653-63), Interleukin-6 (IL-6) (Scheller et al., Biochem Biophysica Acta (BBA)—Molecular Cell Research, May 2011, 1813(5):878-888), Interleukin-8 (IL-8) (Aghazarian et al., Urology, 2015, 86(1):52-56), Interferon gamma (IFN-γ) (Di Bari, Clin Ter, 2015, 166(3)), Tumor necrosis factor alpha (TNF-α) (Roubille et al., Ann Rheum Dis, 2015, 74(3):480-489), and Macrophage Inflammatory Protein 1α (MIP-1α) (Dapunt, Mediators Inflamm, 2014, 2014:728619).
PDE4 inhibition is known to improve therapeutic treatment of a number of inflammatory, respiratory and allergic diseases and conditions (U.S. Pat. No. 6,649,633B2; Keren et al., J Dermatol Sci, January 2015, 77(1):74-76).
Novel and improved compounds and compositions for treating cancers, autoimmune diseases and inflammatory diseases are desirable.